The chemical and biological literature abounds with reports on the benzo[de]isoquinoline-1,3-diones (I) due in great part to their cytotoxic and antitumor activities (Proc. 10th Int. Congress of Chemother., 1977;2:1216; Cancer Chemother. Pharmac., 1980;4:61; Eur. J. Med. Chem., 1981;16:207). Paull, et al. (Arzneim Forsch/Drug Res., 1984;34:1243) performed a retrospective analysis of hundreds of compounds within the benzo[de]isoquinolone-1,3-dione class, and showed that all of their cytotoxic/antitumor biological activity was associated with the presence of an extended amino containing alkyl group at the diimide nitrogen (R2). 
R2 is X(CH2)nN(R)2 
X is O, NH, CH2, or CHR, wherein
R is alkyl.
Longer chains or substituted chains were also tolerated. The cytotoxic/antitumor activities of these agents are mediated by their binding to DNA (Biochem., 1982;21:2070; J. Med. Chem., 1996;39:1609). A number of clinical candidates have been studied for the treatment of tumors and leukemia such as mitonafide (II), amonafide (III), and DMP840 (IV) (Cancer Res., 1994;54:159; Proc. Nat. Acad. Sci., 1995;92:8950). 
As cytotoxic and antitumor agents, compounds such as II-IV also display antibacterial activity (Chatterjee, et al., Proc. Nat. Acad. Sci., 1995;92:8950) and antiparasitic activity (Antimicrob. Agents Chemother., 1996;40:706). Because they bind DNA, they are able to inhibit mammalian and bacterial topoisomerases mediating the ultimate death of the cells (Antimicrob. Agents Chemother., 1996;40:706). As antibacterial agents, these compounds lack specificity and are overly toxic to mammalian cells.
Due to the ever increasing incidence of antibiotic resistance appearing around the world, new antibacterials of novel structure have become very important for the treatment of bacterial infections (J. Med. Chem., 1996;39:3853).
The subject of this invention is the discovery that the antibacterial activity of the benzo[de]isoquinoline-1,3-diones can be effectively separated from the cytotoxic and antitumor activities by the replacement of the alkyl amino group in compounds I-IV with a hydroxyl group (I, R2xe2x95x90OH). These 2-hydroxy benzo[de]isoquinoline-1,3-diones (V) do not strongly intercalate or bind DNA, and in fact, are selective inhibitors of bacterial DNA gyrase and DNA topoisomerase IV. Compounds that inhibit two bacterial targets are expected to offer significant advantages in treatment of bacterial infection by lowering the frequency of bacterial resistance (Cozzarelli, et al., Proc. Natl. Acad. Sci. USA, 1995;92:11801; Hosino, et al., Antimicrobial Agents Chemother., 1994;38:2623). 
wherein R is a general substituent halo, nitro amino and the like.
Certain compounds of the type V have been described in U.S. Pat. No. 5,076,831 as intermediates to Va and as additives in the preparation of herbicidal formulations.
Compounds of type V were reported as synthetic intermediates leading to ring contracted products (J. Med. Chem., 1992;35:663; Zh. Org. Chim., 1977;13:2194). Studies of the base hydrolysis of compounds of type V have also been described (Zh. Org. Chim., 1973;9:171 and 1970;6:1480). X-ray studies of compounds V were reported (Zh. Strut. Khim., 1970;11:939) as well as acylations of the hydroxy group (Zh. Org. Chim., 1972;8:165).
German Patent DE2417789 and U.S. Pat. No. 3,941,791 describes compounds of the Type V as dyes and brighteners. U.S. Pat. No. 4,007,192 refers to a process of preparing the 6,7-dicarboxylic acids of compound V. U.S. Pat. No. 3,880,859 reports a wide variety of O-alkyl analogs (Va) as fiber whiteners. There were no claims or disclosures of any antibacterial activity in any of the references cited above.
The instant invention is a compound of formula 
or a pharmaceutically acceptable salt thereof wherein:
R is hydrogen or a protecting group typically used in the art for protecting alcohols: benzyl, 4-methoxybenzyl, methyl, acetyl, benzoyl, 2,2,2-trichloroethyl, t-butyldimethylsilyl, t-butyl, and allyl;
R1-R5 are each independently chosen from H, Cl, Br, F, a straight or branched alkyl of 1-8 carbons, a cycloalkyl of 3-8 carbons, a heterocycle or bridged heterocycle of 4-9 atoms containing 1-3 heteroatoms, xe2x80x94(CRxe2x80x22)nOR6, xe2x80x94(CRxe2x80x22)nN(R6)2, xe2x80x94(CRxe2x80x22)nNR6COR7, xe2x80x94(CRxe2x80x22)nNR6SO2OR7, xe2x80x94(CRxe2x80x22)nNR6SO2N(R6)2, xe2x80x94(CRxe2x80x22)nOSO2N(R6)2, xe2x80x94(CRxe2x80x22)nCN, xe2x80x94(CRxe2x80x22)nC(NOR6)R7, NO2, CF3, xe2x80x94(CRxe2x80x22)nSOmR7, xe2x80x94(CRxe2x80x22)nCO2R6, xe2x80x94(CRxe2x80x22)nCON(R6)2, Ph, and any two of R1-R5 may form a substituted or unsubstituted ring of 5-7 total atoms having 0-2 heteroatoms;
n is an integer of from 0 to 5;
m is an integer of from 0 to 3;
R6 and R7 are independently hydrogen, a straight or branched alkyl of 1-6 carbons, a cycloalkyl of 3-6 carbons, a heterocycle of 5-6 atoms with 1-3 heteroatoms, or Ph, all of which may be optionally substituted;
R8 is a cycloalkyl of 3-7 carbons or a heterocycle of 4-9 atoms with 1-4 heteroatoms;
Rxe2x80x2 is R6, F, Br, Cl, OR6, N(R6)2, and any two R""s may form a ring of 3-6 total atoms with 0-2 heteroatoms;
wherein the alkyls, cycloalkyls, heterocycles, and Ph recited above may be optionally substituted; and
wherein the substituents are selected from a straight or branched alkyl of 1-4 carbons, Br, F, Cl, xe2x80x94(CRxe2x80x22)nOR6, xe2x80x94(CRxe2x80x22)nN(R6)2, xe2x80x94(CRxe2x80x22)nNR6COR7, xe2x80x94(CRxe2x80x22)nNR6SO2OR7, xe2x80x94(CRxe2x80x22)nNR6SO2N(R6)2, xe2x80x94(CRxe2x80x22)nOSO2N(R6)2, xe2x80x94(CRxe2x80x22)nCN, xe2x80x94(CRxe2x80x22)nC(NOR6)R7, NO2, CF3, xe2x80x94(CRxe2x80x22)nSOmR7, xe2x80x94(CRxe2x80x22)nCO2R6, xe2x80x94(CRxe2x80x22)nR8, xe2x80x94(CRxe2x80x22)nCON(R6)2, and Ph.
Preferred compounds of the invention are those of Formula I above wherein
R is selected from
hydrogen,
benzyl,
4-methoxybenzyl,
methyl,
acetyl,
benzoyl,
2,2,2-trichloroethyl,
t-butyldimethylsilyl,
t-butyl,
allyl, and
trimethylsilyl;
R1, R2, R3, R4, and R5 are each independently selected from
hydrogen,
chlorine,
bromine,
fluorine,
straight or branched alkyl of from 1-8 carbons,
cycloalkyl of from 3-8 carbons,
heterocycle of from 4-8 atoms having from 1-3 heteroatoms,
xe2x80x94(CRxe2x80x22)nOR6,
(CRxe2x80x22)nN(R6)2,
xe2x80x94(CRxe2x80x22)nNR6COR7,
(CRxe2x80x22)nNR6SO2OR7,
xe2x80x94(CRxe2x80x22)nNR6SO2N(R6)2,
(CRxe2x80x22)nOSO2N(R6)2,
(CRxe2x80x22)nCN,
xe2x80x94(CRxe2x80x22)nC(NOR6)R7,
xe2x80x94NO2,
xe2x80x94(CRxe2x80x22)nSOmR7,
xe2x80x94CF3,
xe2x80x94(CRxe2x80x22)nCO2R6,
xe2x80x94(CRxe2x80x22)nCON(R6)2,
-phenyl;
wherein n is an integer from 0 to 5;
m is an integer of from 0 to 3; and
R6 and R7 are each independently selected from
hydrogen,
straight or branched alkyl of from 1-6 carbons,
cycloalkyl of from 3-6 carbons,
heterocycle of from 5-6 atoms having from 1-3 heteroatoms, or
phenyl;
R8 is a heterocycle of 5 or 6 atoms with 1 or 2 heteroatoms;
Rxe2x80x2 is hydrogen,
fluorine,
chlorine,
bromine,
OR6, or
N(R6)2 wherein R6 is alkyl; and
each of alkyl, cycloalkyl, heterocycle, and phenyl above is each independently unsubstituted or substituted with from 1-3 substituents selected from:
methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, t-butyl, F, Cl, Br, CF3, CN, COCH3, CO2H, CONH2, C(Rxe2x80x22)nN(R6)2, C(Rxe2x80x22)nOR6, NO2, NR6COR6, CO2R6, or OCOR6.
More preferred compounds of the invention are those of Formula I above wherein any two of R1-R5 may form a substituted or unsubstituted ring of from 5-7 atoms having from 0-2 heteroatoms selected from oxygen, sulfur, and nitrogen.
Still more preferred compounds of the invention are those of Formula I above wherein
R is H, benzyl, 4-methoxybenzyl, methyl, acetyl, allyl, benzoyl, 2,2,2-trichloroethyl, or t-butyldimethylsilyl and any R1-R5 may be chosen from F, Cl, Br, OMe, and a substituted or unsubstituted piperidine, morpholine, piperazine, pyrrolidine, or thiomorpholine.
Most preferred compounds of the invention are those of Formula I above wherein
R is H;
R1-R5 is H, Cl, Br, F, OCH3, NO2, or CH3 and at least one R1-R5 is a heterocycle.
Still other most preferred compounds of the invention are those of Formula I above wherein
R is H;
R1-R5 is H, Cl, Br, F, OCH3, NO2, or CH3 and at least one R1-R5 is 3- or 4-amino-piperidin-1-yl, 3- or 4-aminomethyl-piperidin-1-yl, 3-amino or 3-aminomethyl-pyrrolidin-1-yl, 3-amino or 3-aminomethyl-azetidinyl-1-yl, [S-(R*,S*)]-3-(1-aminoethyl)-pyrrolidin-1-yl, trans-3-amino-4-methyl-pyrrolidin-1-yl, 6-amino-3-azo-bicyclo[3.1.0]hex-3-yl, or octahydro-1H-pyrrolo[3,4-b]pyridin-6-yl.
Still other most preferred compounds of the invention are those of Formula I above wherein
R is H;
R2 is halogen at the five position;
R3 is heterocycle at the six position which heterocycle is selected from an unsubstituted or substituted piperazinyl, morpholinyl, pyrrolidinyl, azetidinyl, bicyclo[3.1.0]hex-1-yl, 2-azabicyclo[4.3.0]nonane-2-yl, and piperidinyl;
which substituents are one or more selected from xe2x80x94(CRxe2x80x22)nOR6, xe2x80x94(CRxe2x80x22)nN(R6)2, xe2x80x94(CRxe2x80x22)nNR6COR7, xe2x80x94(CRxe2x80x22)nNR6SO2OR7, xe2x80x94(CRxe2x80x22)nNR6SO2N(R6)2, xe2x80x94(CRxe2x80x22)nOSO2N(R6)2, xe2x80x94(CRxe2x80x22)nCN, xe2x80x94(CRxe2x80x22)nC(NOR6)R7, NO2, xe2x80x94(CRxe2x80x22)nSOmR7, xe2x80x94(CRxe2x80x22)nCO2R6, xe2x80x94(CRxe2x80x22)nCON(R6)2, Ph, and F, Cl, and Br; and
R4 and R5 are each hydrogen.
Other most preferred compounds of the invention are those according to Formula I and selected from:
2-Hydroxy-5-nitro-benzo[de]isoquinoline-1,3-dione;
2-Hydroxy-6-nitro-benzo[de]isoquinoline-1,3-dione;
2,5-Dihydroxy-benzo[de]isoquinoline-1,3-dione;
6-Bromo-2-hydroxy-benzo[de]isoquinoline-1,3-dione;
6-Chloro-2-hydroxy-benzo[de]isoquinoline-1,3-dione;
6-Amino-2-hydroxy-benzo[de]isoquinoline-1,3-dione;
5-Amino-2-hydroxy-benzo[de]isoquinoline-1,3-dione;
5-Acetamido-N-2-hydroxy-benzo[de]isoquinoline-1,3-dione;
5-Trifluoromethanesulfonyloxy-2-hydroxy-benzo[de]isoquinoline-1,3-dione;
5-Fluoro-2-hydroxy-benzo[de]isoquinoline-1,3-dione;
6-Fluoro-2-hydroxy-benzo[de]isoquinoline-1,3-dione;
2-Hydroxy-5-methoxy-benzo[de]isoquinoline-1,3-dione;
5-Ethoxy-2-hydroxy-benzo[de]isoquinoline-1,3-dione;
2-Hydroxy-6-methylthio-benzo[de]isoquinoline-1,3-dione;
2-Hydroxy-6-methoxy-benzo[de]isoquinoline-1,3-dione;
2-Hydroxy-5-methyl-benzo[de]isoquinoline-1,3-dione;
5-(2-Dimethylamino-ethoxy)-2-hydroxy-benzo[de]isoquinoline-1,3-dione;
2-Hydroxy-5-(2-acetoxy-ethoxy)-benzo[de]isoquinoline-1,3-dione;
2-Hydroxy-5-(2-hydroxy-ethoxy)-benzo[de]isoquinoline-1,3-dione;
2-Hydroxy-5-(2-carboxy-ethoxy)-benzo[de]isoquinoline-1,3-dione;
6-Amino-5-bromo-2-hydroxy-benzo[de]isoquinoline-1,3-dione;
6-Amino-5-chloro-2-hydroxy-benzo[de]isoquinoline-1,3-dione;
5-Amino-6-chloro-2-hydroxy-benzo[de]isoquinoline-1,3-dione;
2,5-Dihydroxy-6-nitro-benzo[de]isoquinoline-1,3-dione;
6-Amino-2-hydroxy-5-methoxy-benzo[de]isoquinoline-1,3-dione;
5-Bromo-2-hydroxy-6-methoxy-benzo[de]isoquinoline-1,3-dione;
6-Bromo-2-hydroxy-5-methoxy-benzo[de]isoquinoline-1,3-dione;
6-(2-Chloroacetamido)-methyl-2,5-dihydroxy-benzo[de]isoquinoline-1,3-dione;
6-Aminomethyl-2,5-dihydroxy-benzo[de]isoquinoline-1,3-dione, hydrochloride;
6-Acetamidomethyl-2,5-dihydroxy-benzo[de]isoquinoline-1,3-dione;
6-Acetamidomethyl-2-hydroxy-5-methoxy-benzo[de]isoquinoline-1,3-dione;
6-Aminomethyl-2-hydroxy-5-methoxy-benzo[de]isoquinoline-1,3-dione;
2-Hydroxy-5,8-dinitro-benzo[de]isoquinoline-1,3-dione;
5,8-Diamino-2-hydroxy-benzo[de]isoquinoline-1,3-dione;
5,8-Diacetamido-2-hydroxy-benzo[de]isoquinoline-1,3-dione;
2-Hydroxy-5-methoxy-6-nitro-benzo[de]isoquinoline-1,3-dione; and
2-Hydroxy-6,7-dinitro-benzo[de]isoquinoline-1,3-dione.
Other most preferred compounds of the invention are selected from:
2-Hydroxy-6-(4-methyl-piperazin-1-yl)-benzo[de]isoquinoline-1,3-dione;
2-Hydroxy-6-(pyrrolidin-1-yl)-benzo[de]isoquinoline-1,3-dione;
2-Hydroxy-6-(morpholin-4-yl)-benzo[de]isoquinoline-1,3-dione;
2-Hydroxy-6-(piperidin-1-yl)-benzo[de]isoquinoline-1,3-dione;
2-Hydroxy-5-methoxy-6-(4-methyl-piperazin-1-yl)-benzo[de]isoquinoline-1,3-dione, hydrochloride;
2-Hydroxy-5-methoxy-6-(pyrrolidin-1-yl)-benzo[de]isoquinoline-1,3-dione;
2-Hydroxy-5-methoxy-6-(piperidin-1-yl)-benzo[de]isoquinoline-1,3-dione;
2-Hydroxy-5-methoxy-6-(morpholin-4-yl)-benzo[de]isoquinoline-1,3-dione;
5-Hydroxy-11H-8,10-dioxa-5-aza-benzo[de]anthracene-4,6-dione;
5-Hydroxy-11H, 11-methoxy-8,10-dioxa-5-aza-benzo[de]anthracene-4,6-dione;
5-Bromo-2-hydroxy-6-(piperidine-1-yl)-benzo[de]isoquinoline-1,3-dione;
5-Bromo-2-hydroxy-6-(4-methylpiperazin-1-yl)-benzo[de]isoquinoline-1,3-dione;
5-Bromo-2-hydroxy-6-(3-methylpiperidin-1-yl)-benzo[de]isoquinoline-1,3-dione;
5-Bromo-2-hydroxy-6-(pyrrolidin-1-yl)-benzo[de]isoquinoline-1,3-dione;
5-Bromo-6-dimethylamino-2-hydroxy-benzo[de]isoquinoline-1,3-dione;
(S)-6-(3-Amino-pyrrolidin-1-yl)-5-bromo-2-hydroxy-benzo[de]isoquinoline-1,3-dione, hydrochloride;
5-Cyano-2-hydroxy-6-(piperidin-1-yl)-benzo[de]isoquinoline-1,3-dione;
5-Cyano-2-hydroxy-6-(morpholin-1-yl)-benzo[de]isoquinoline-1,3-dione;
5-Cyano-2-hydroxy-6-(pyrrolidin-1-yl)-benzo[de]isoquinoline-1,3-dione;
(S)-6-(3-Amino-pyrrolidin-1-yl)-5-cyano-2-hydroxy-benzo[de]isoquinoline-1,3-dione, hydrochloride;
5-Bromo-2-hydroxy-7-(pyrrolidin-1-yl)-benzo[de]isoquinoline-1,3-dione;
2-Hydroxy-5-methyl-7-(pyrrolidin-1-yl)-benzo [de]isoquinoline-1,3-dione;
5-Bromo-2-hydroxy -7-(piperidin-1-yl)-benzo[de]isoquinoline-1,3-dione;
6-(3-Amino-pyrrolidin-1-yl)-2-hydroxy-benzo[de]isoquinoline-1,3-dione;
6-(3-Amino-pyrrolidin-1-yl)-2-hydroxy-5-methoxy-benzo[de]isoquinoline-1,3-dione;
5-Acetamido-2-hydroxy-6-(pyrrolidin-1-yl)-benzo[de]isoquinoline-1,3-dione;
5-Amino-2-hydroxy-6-(pyrrolidin-1-yl)-benzo[de]isoquinoline-1,3-dione;
2-Hydroxy-5-nitro-6-(pyrrolidin-1-yl)-benzo[de]isoquinoline-1,3-dione;
5-Chloro-2-hydroxy-6-[3-methoxypyrrolidin-1-yl]-benzo[de]isoquinoline-1,3-dione;
6-(3-Amino-azetidin-1-yl)-5-chloro-2-hydroxy-benzo[d,e]isoquinoline-1,3-dione;
4-Amino-6-(3-amino-azetidin-1-yl)-7,8-dibromo-5-chloro-2-hydroxy-benzo[d,e]isoquinolone-1,3-dione;
5,6-Dichloro-2-hydroxy-benzo[de]isoquinoline-1,3-dione;
6-Bromo-5-methyl-2-hydroxy-benzo[de]isoquinoline-1,3-dione;
6,8-Dibromo-2-hydroxy-5-methyl-benzo[de]-isoquinoline-1,3-dione;
2-Hydroxy-6,7-dinitro-5-methoxy-benzo[de]isoquinoline-1,3-dione;
6,7-Diamino-2-hydroxy-5-methoxy-benzo[de]isoquinoline-1,3-dione;
5-Bromo-2-hydroxy-6-nitro-benzo[de]isoquinoline-1,3-dione;
5-Bromo-6,7-dinitro-2-hydroxy-benzo[de]isoquinoline-1,3-dione;
2-Hydroxy-8-nitro-6-(pyrrolidin-1-yl)-benzo[de]isoquinoline-1,3-dione;
2-Hydroxy-5,8-dinitro-6-(pyrrolidin-1-yl)-benzo[de]isoquinoline-1,3-dione;
5-Hydroxy-9-methyl-10H-5,8,10-triaza-cyclopenta[a]phenalene-4,6-dione;
5-Chloro-2-hydroxy-8-nitro-6-(pyrrolidin-1-yl)-benzo[de]isoquinoline-1,3-dione;
5,6-Dichloro-2-hydroxy-7-(pyrrolidin-1-yl)-benzo[de]-isoquinoline-1,3-dione;
2,5-Dihydroxy-2,3-dihydro-1,3-dioxo-1H-benzo[de]isoquinoline-6-carboxaldehyde;
6-Hydroxyiminomethyl-2,5-dihydroxy-benzo[de]isoquinoline-1,3-dione;
2-Hydroxy-5,6-dimethoxy-benzo[de]isoquinoline-1,3-dione;
2-Hydroxy-5,6-methylenedioxy-benzo[de]isoquinoline-1,3-dione;
5-Hydroxy-9H, 10H-8,11-dioxa-5-aza-benzo[de]anthracene-4,6-dione;
5-Hydroxy-8H-9,11-dioxa-5-aza-benzo[de]anthracene-4,6-dione;
6-Bromo-2,5-dihydroxy-benzo[de]isoquinoline-1,3-dione;
5-Hydroxy-10-methyl-9,10-dihydro-8-oxa-5,10-diaza-cyclopenta[a]phenalene-4,6-dione;
5,10-Diaza-8-oxa-benzo[de]anthracene-4,6-dione;
2,5-Dihydroxy-6-(piperidin-1-yl)-methyl-benzo[de]isoquinoline-1,3-dione;
5-Fluoro-2-hydroxy-6-(pyrrolidin-1-yl)-benzo[de]isoquinoline-1,3-dione;
2-Hydroxy-4-methoxy-benzo[de]isoquinoline-1,3-dione;
8-Amino-2-hydroxy-4-methoxy-benzo[de]isoquinoline-1,3-dione;
8-Bromo-5-chloro-6-(pyrrolidin-1-yl)-benzo[de]isoquinoline-1,3-dione; and
4-Amino-7-(3-amino-pyrrolidin-1-yl)-2-hydroxy-5,6,8-trichloro-benzo[d,e]isoquinoline-1,3-dione.
The instant invention is also a pharmaceutical composition which comprises an antibacterially effective amount of a compound for Formula I or a pharmaceutically acceptable salt thereof with a pharmaceutically acceptable carrier.
The invention further includes a method for treating bacterial infection in a mammal which comprises administering to said mammal an antibacterially effective amount of a compound of Formula I or a pharmaceutical composition of the same to a mammal in need thereof.
The invention further includes a method of selectively inhibiting bacterial DNA gyrase and DNA topoisomerase in a mammal in need of said inhibition which comprises administering to said mammal a compound of Formula I.
The invention further includes novel intermediates of formula 
wherein R1-R5 are as defined above, and one of R1-R5 is a leaving group selected from halogen, OMe, NO2, and triflate which leaving group is suitable for displacement by a nitrogen heterocycle.
The terms describing the compounds of the instant invention are as follows:
Alcohol protecting groups are benzyl, 4-methoxybenzyl, methyl, acetyl, benzoyl, 2,2,2-trichloroethyl, t-butyldimethylsilyl, trimethylsilyl, t-butyl, allyl, or as described in Greene, Theodora W., Protective Groups in Organic Synthesis, 1991:1-9.
The alkyl groups of the invention are both straight and branched carbon chains of from 1-8 carbon atoms. Representative of such groups are methyl, ethyl, propyl, isopropyl, and the like.
The cycloalkyl groups of the invention are those having 3-8 carbon atoms such as cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.
Heterocycle is a cyclic, bicyclic ring or bridged system having from 4-10 atoms, from one to four of which are selected from O, S, and N. Heterocycle includes non-aromatic groups such as morpholino and pyrrolidino. Preferred heterocycles are 5- or 6-membered mono-cyclic aromatic rings having 1 or 2 heteroatoms. Heterocycle also includes bicyclic rings such as benzofuran, isothiazolone, indole, and the like. Heterocycle also includes bridged ring systems. Typical groups represented by the term include: 
wherein the hyphen indicates the point of attachment. The groups above and below are optionally substituted on the peripheral nitrogens by alkyl groups as defined above or by nitrogen protecting groups as described by Green (referenced above). Other typically preferred groups include pyrimidine, pyridazine, pyrazine, oxazole, pyrazole, thiazole, and the like. Most preferred are: piperazine, pyrrolidine, morpholine, thiomorpholine, thiazole, oxazole, isoxazole, piperidine, and azetidine.
Any two of the R1-R5 groups can form a ring of from 5-7 atoms (this ring includes the carbons to which the R1-R5 group is attached). Such rings are: dioxalane, benzoxazine, indane, 1,3-benzodioxole, 2,3-dihydrobenzoxazole, 2,3-dihydrobenzofuran, 2,3-dihydro-1H-isoindole, 1,3-dihydroisofuran, 1,3-benzoxathiazole, 2,3-dihydro-1H-indole, 2,3-dihydro-1,4-benzodioxin, 3,4-dihydro-2H-1,4-benzoxazine, 3,4-dihydro-2H-1,3-benzoxazine, 4H-1,3-benzodioxin, 3,4-dihydro-2H-1-benzopyran, 3,4-dihydro-1H-2-benzopyran, 1,2,3,4-tetrahydroquinoxaline, 1,2,3,4-tetrahydroisoquinoline, 2,3-dihydro-1,4-benzoxathinindane, 1,2,3,4-tetrahydronaphthalene, and the like.
The Rxe2x80x2 group is R6, hydrogen, a straight or branched alkyl of 1-6 carbons, a cycloalkyl of 3-6 carbons, a heterocycle of 5-6 atoms with 1-3 heteroatoms, phenyl, all of which may be unsubstituted or substituted as discussed below. Rxe2x80x2 is also F, Br, Cl, OR6, or N(R6)2. Any two Rxe2x80x2 groups can form a ring having from 3-6 atoms having from 0-2 heteroatoms including a spirocycle which is a carbocyclic or heterocyclic ring whose ends meet at a single carbon in a chain or another ring.
Each of the terms above (alkyl, cycloalkyl, heterocycle, and the phenyl group) can be unsubstituted or substituted with from 1-3 substituents. The substituents are selected from: a straight or branched alkyl of 1-4 atoms such as methyl, ethyl, isopropyl, sec-butyl, t-butyl, F, Cl, Br, xe2x80x94(CRxe2x80x22)nOR6, xe2x80x94(CRxe2x80x22)nN(R6)2, xe2x80x94(CRxe2x80x22)nNR6COR7, xe2x80x94(CRxe2x80x22)nNR6SO2OR7, xe2x80x94(CRxe2x80x22)nNR6SO2N(R6)2, xe2x80x94(CRxe2x80x22)nOSO2N(R6)2, xe2x80x94(CRxe2x80x22)nCN, xe2x80x94(CRxe2x80x22)nC(NOR6)R7, NO2, xe2x80x94(CRxe2x80x22)nSOmR7, xe2x80x94(CRxe2x80x22)nCO2R6, xe2x80x94(CRxe2x80x22)nCON(R6)2, and Ph.
The compounds of the invention are capable of forming both pharmaceutically acceptable acid addition and/or base salts. Base salts are formed with metals or amines, such as alkali and alkaline earth metals or organic amines. Examples of metals used as cations are sodium, potassium, magnesium, calcium, and the like. Examples of suitable amines are N,Nxe2x80x2-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, N-methylglucamine, and procaine.
Pharmaceutically acceptable acid addition salts are formed with organic and inorganic acids.
Examples of suitable acids for salt formation are hydrochloric, sulfuric, phosphoric, acetic, citric, oxalic, malonic, salicyclic, malic, gluconic, fumaric, succinic, ascorbic, maleic, methanesulfonic, and the like. The salts are prepared by contacting the free base form with a sufficient amount of the desired acid to produce either a mono or di, etc. salt in the conventional manner. The free base forms may be regenerated by treating the salt form with a base. For example, dilute solutions of aqueous base may be utilized. Dilute aqueous sodium hydroxide, potassium carbonate, ammonia, and sodium bicarbonate solutions are suitable for this purpose. The free base forms differ from their respective salt forms somewhat in certain physical properties such as solubility in polar solvents, but the salts are otherwise equivalent to their respective free base forms for purposes of the invention. Use of excess base where Rxe2x80x2is hydrogen gives the corresponding basic salt.
The compound of the invention can exist in unsolvated as well as solvated forms, including hydrated forms. In general, the solvated forms, including hydrated forms and the like are equivalent to the unsolvated forms for purposes of the invention.
Certain compounds of the invention may exist in optically active forms. The pure D isomer, pure L isomer, as well as mixtures thereof, including the racemic mixtures, are contemplated by the invention. Additional asymmetric carbon atoms may be present in a substituent such as an alkyl group. All such isomers as well as mixtures thereof are intended to be included in the invention.
The compounds of the invention can be prepared and administered in a wide variety of oral and parenteral dosage forms. It will be obvious to those skilled in the art that the following dosage forms may comprise as the active component, either a compound of Formula I or a corresponding pharmaceutically acceptable salt of a compound of Formula I.
For preparing pharmaceutical compositions from the compounds described by this invention, inert, pharmaceutically acceptable carriers can be either solid or liquid. Solid form preparations include powders, tablets, dispersible granules, capsules, cachets, and suppositories. A solid carrier can be one or more substances which may also act as diluents, flavoring agents, solubilizers, lubricants, suspending agents, binders, or tablet disintegrating agents; it can also be an encapsulating material. In powders, the carrier is a finely divided solid which is in admixture with the finely divided active compound. In the tablet the active compound is mixed with carrier having the necessary binding properties in suitable proportions and compacted in the shape and size desired. The powders and tablets preferably contain from 5 or 10 to about 70 percent of the active ingredient. Suitable solid carriers are magnesium carbonate, magnesium stearate, talc, sugar, lactose, pectin, dextrin, starch, gelatin, tragacanth, methyl cellulose, sodium carboxymethyl cellulose, a low melting wax, cocoa butter, and the like. The term xe2x80x9cpreparationxe2x80x9d is intended to include the formulation of the active compound with encapsulating material as carrier providing a capsule in which the active component (with or without other carriers) is surrounded by carrier, which is thus in association with it. Similarly, cachets are included. Tablets, powders, cachets, and capsules can be used as solid dosage forms suitable for oral administration.
Liquid form preparations include solutions, suspensions, and emulsions. As an example may be mentioned water or water-propylene glycol solutions for parenteral injection. Such solutions are prepared so as to be acceptable to biological systems (isotonicity, pH, etc.). Liquid preparations can also be formulated in solution in aqueous polyethylene glycol solution. Aqueous solutions suitable for oral use can be prepared by dissolving the active component in water and adding suitable colorants, flavors, stabilizing, and thickening agents as desired. Aqueous suspension suitable for oral use can be made by dispersing the finely divided active component in water with viscous material, i.e., natural or synthetic gums, resins, methyl cellulose, sodium carboxymethyl cellulose, and other well-known suspending agents.
Topical treatment includes formulations with a vehicle, a base or carrier, carefully selected for the active ingredient. Ointments, creams, lotions, and solutions are included.
Preferably, the pharmaceutical preparation is in unit dosage form. In such form, the preparation is subdivided into unit doses containing appropriate quantities of the active component. The unit dosage form can be a packaged preparation, the package containing discrete quantities of preparation, for example, packeted tablets, capsules, and powders in vials or ampoules. The unit dosage form can also be a capsule, cachet, or tablet itself or it can be the appropriate number of any of these packaged forms.
The quantity of active compound in a unit dose of preparation may be varied or adjusted from 1 mg to 100 mg according to the particular application and the potency of the active ingredient.
In therapeutic use as agents for treating bacterial infections, the compounds utilized in the pharmaceutical method of this invention are administered at the initial dosage of about 3 mg to about 40 mg per kilogram daily. A daily dose range of about 6 mg to about 14 mg per kilogram is preferred. The dosages, however, may be varied depending upon the requirements of the patient, the severity of the condition being treated, and the compound being employed. Determination of the proper dosage for a particular situation is within the skill of the art. Generally, treatment is initiated with smaller dosages which are less than the optimum dose of the compound. Thereafter, the dosage is increased by small increments until the optimum effect under the circumstances is reached. For convenience, the total daily dosage may be divided and administered in portions during the day, if desired. Antibacterial agents can also be used as injectables as in injections for open wounds.
The compounds of the present invention may be prepared through a combination of electrophilic/nucleophilic reactions typically associated with benzene and naphthalene chemistry. This chemistry may be performed on a suitably substituted 1,8-napthalic anhydride 1, which is subsequently converted to the desired 2-hydroxy-benzo[de]isoquinoline-1,3-dione compound 3. Alternatively, the chemical manipulations may be performed directly on the 2-hydroxy-benzo[de]isoquinoline-1,3-dione itself or on a suitably protected derivative 2. The conversion of the anhydrides 1 to the isoquinoline diones is shown in Scheme 1 below. 
wherein
R is one or more from R1-R5 in Schemes 1-4 and 6-9.
An O-protected hydroxylamine is reacted with the anhydride at 20-100xc2x0 C. in an alcoholic solvent such as methanol or ethanol with the addition of an inert base such as triethylamine (TEA) or 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU). Aqueous alcohol may also be employed in mixtures varying in the percent alcohol based on solubility of the anhydride. Inert bases may be added or a suitable metal hydroxide such as sodium hydroxide may be used. Still other solvents such as pyridine or dimethylformamide may be employed. The protecting groups employed for the hydroxylamine are generally those typically used for alcohol protection and include benzyl, 4-methoxy benzyl, 3,3,3-trichloroethyl, t-butyl, acetyl, allyl and the like. The protecting groups are generally removed to give 3 with acid, base, or with hydrogenation with palladium on carbon (Pd/C) support. Protecting groups and their removal are chosen to be compatible with the substituents R. Typical acids are hydrochloric acid and trifluoroacetic acid and a typical base is sodium hydroxide. Alternatively, hydroxylamine hydrochloride may be used directly to convert 1 to 3. Typical solvents are alcohols, acetic acid, or pyridine and reaction temperatures are generally 20-120xc2x0 C.
The 2-hydroxy-benzo[de]isoquinoline-1,3-diones may themselves be protected to enable certain chemical reactions or to enhance solubility (Scheme 2). 
Again, the type of protecting group and its synthesis and removal are generally typical of alcohol chemistry. The protecting groups are represented by Rxe2x80x3X where X is a leaving group such as chlorine, bromine, or acetate. Rxe2x80x3 may be an alkyl based group such as benzyl or 4-methoxy benzyl; an acyl group such as acetyl or benzoyl; or one of several silicon based protecting groups such as trimethyl silyl or t-butyl-dimethylsilyl. The benzyl groups are generally reacted with 3 at 0-100xc2x0 C. in alcoholic solvent or acetone in the presence of base such as TEA, DBU, sodium carbonate, cesium carbonate or the like. The acyl groups are added to 3 at 0-100xc2x0 C. using acetyl chloride or acetic anhydride, neat or in inert solvent like benzene, toluene, or methylene chloride. Excess reagent is generally employed and inert bases may be used. The trimethyl silyl or t-butyl-dimethyl silyl are generally added to 3 as their chlorides at 0-50xc2x0 C. in chlorocarbon solvents such as chloroform or dichloromethane using an inert base such as TEA or the like. The benzyl groups may be removed with hydrogenation using Pd/C or by strong acids such as HBr, HI and the like. Boron tristrifluoroacetate may be used to also cleave benzyl and allyl groups. Allyl groups may also be removed by PhSiH3 with Pdxc2x0 catalyst. The acetyl groups are removed preferably by aqueous bases such as sodium hydroxide, with alcohol added as needed for solubility at temperatures of 25-100xc2x0 C. The silyl protecting groups may be removed by acids such as HCl, bases such as sodium hydroxide, or by fluoride ion using CsF and the like.
The electrophilic chemistry used to prepare the targeted compounds follows the electrophilic chemistry known for benzene and naphthalene. Each electrophile, once on the ring, helps direct the next electrophile to a specific position. The nitrations are typically conducted on the anhydride 1 and are shown in Scheme 3. These are typically performed at 0-150xc2x0 C. using sulfuric acid and nitric acid in ratios of 2.5:1, or in glacial acetic acid and nitric acid in a ratio approximately of 10:1. The products 5 or 6 are determined by the R substituent. If the R substituent is a donating group product 6 generally predominates; if R is a withdrawing group, product 5 generally predominates. A specific example is the conversion of 7 to 8 which occurs using sulfuric acid/nitric acid. When fuming nitric acid (stronger conditions) is employed with sulfuric acid and heat, the nitration occurs at the 7-position to give a mixture of 8 and 9. Other examples of regioselective nitrations are the conversion of 10 to 11 and the conversion of 12 to 13. 
In Scheme 4 typical halogenations are shown. Brominations may be accomplished at 10-100xc2x0 C. with Br2 or N-bromosuccinimide in halocarbon solvents such as chloroform or dichloromethane, dioxane, or in acetic acid solvent. If more rigorous conditions are required, catalysts such as iron or AlBr3 may be added and the reactions performed in aqueous alcohol (for iron) or carbon disulfide or halocarbon (for AlBr3). Chlorinations are performed using sulfuryl chloride (SO2Cl2) at 30-100xc2x0 C., neat or in inert solvent such as nitrobenzene or chlorocarbon solvents or with N-chlorosuccinimide in halocarbon solvents. Halogenations may be performed on the anhydride 1 or with the 2-hydroxy derivatives 2 or 3. 
Formylations and aminoformylations are performed when R is a donating substituent as when R is OH in Scheme 5. Formylations are carried out on the anhydrides such as 17a at 25-100xc2x0 C. using aqueous formaldehyde and acid or paraformaldehyde suspended in acid. Alcohol, dioxane, or tetrahydrofuran may be added as required for solubility. The hydroxymethyl compounds such as 18 may be isolated or permitted to react further to give 19a. Alternatively, the formylations may be performed with an added nucleophile. Thus, 17b can be treated with formaldehyde and an amine at 25-100xc2x0 C. over several hours (4-96 hours) to give compounds such as 19b. 
In a similar manner, N-hydroxymethylacetamide will react with activated rings such as 20 at 10-80xc2x0 C. to add N-acetyl methylene to the aromatic ring. Amino formylations are also performed using the amine and formaldehyde under conditions described for the formylation above.
Nucleophilic reactions may be performed on halide, triflate, nitro and alkoxy substituents (represented by L) which are para or ortho to electron withdrawing groups. Such displacements (Scheme 6) are generally carried out on the isoquinoline diones 22 where R and Rxe2x80x3 are defined as substituents chosen from the R1-R5 specifications at temperatures of 25-180xc2x0 C. using a nucleophile neat or in an inert solvent. 
The product 23 may be deprotected as necessary by the methods described above. the typical nucleophile would be an amine as shown in the conversion of 24 to 25 or an alkoxide (26 to 27) or thiol anion (26 to 28). When amines are employed, a co-base such as DBU, aids the reaction. The alkoxide reactions of 26 to 27 or the thiol anion reactions of 26 to 28 are performed in alcoholic solvents. The alkoxides and thioates are prepared by normal methods in the art.
Halides 29a or triflates 29b may also be replaced by alkyl groups to give 30a, b as shown in Scheme 7. Dimethyl zinc is employed with Pd catalyst at 25xc2x0 C. using inert etheral solvents such as tetrahydrofuran and diethyl ether to give 30a or palladium tin couplings may be performed following chemistry well-known in the art to produce 30b where Y is an alkyl group. 
Some 1,8-naphthalic anhydrides are often commercially available or may be prepared according to literature procedures and those described above. Certain 1,8-naphthalic anhydrides may be prepared by total synthesis using Schemes 8 and 9. The acenaphthenes 31 may be reacted with electrophiles as described above for 1. However, the orientation of the incoming electrophile will be different for 31 because the ethylene ring directs differently than the anhydride based ring of 1. 
Once the electrophile has been added and transformed if desired to give 32, 32 is oxidized to the anhydride 33. The oxidations employ KMnO4, Na2Cr2O7, CrO3 and the like and are performed at 0-100xc2x0 C. in AcOH, aqueous sulfuric acid, and as suspensions in organic solvents such as benzene/water. One advantage of this route is it enables the introduction of xe2x80x9cExe2x80x9d to the 2 and 7 positions of the anhydride 33 (positions adjacent to the anhydride grouping). 
Alternatively, naphthalenes such as 34 (Scheme 9) may be reacted with oxalyl chloride or oxalyl bromide and a catalyst according to xe2x80x9cFriedel Craftsxe2x80x9d conditions which are well-known in the art to prepare the diketones 35. Typical catalysts would be AlCl3, TiCl4, BF3 and the like. The reactions are carried out in a carbon disulfide, nitrobenzene or halocarbon solvents at xe2x88x9220xc2x0 C. to 100xc2x0 C. The product 35 is then oxidized similar to the conditions described for 32 to give 36. In addition, periodate oxidations and peracid oxidations which are well-known in the art may be used to convert 35 to 36.
The compounds prepared by the electrophilic or nucleophilic reactions described above may all be further modified by alkylation, acylation, oxidation and reductions that are all typical of organic chemistry functional group modification. For example, nitro compounds may be reduced to amines with H2 with Pd/C or with SnCl2 or iron filings and acid at 25-100xc2x0 C. in inert alcoholic or aqueous alcoholic solvents. The amines may be diazotized with sodium nitrite at low temperatures and may be converted to fluoride, bromide, chloride, phenol, and CN, all by chemistry well-known in the art.